Recently, as the number of patients with Alzheimer's-type dementia has increased along with the growth of the elderly population, patient care has emerged as a serious social problem, and anti-dementia drugs have been developed rapidly. Donepezil hydrochloride having inhibitory effect on acetylcholine esterase has been widely used as a therapeutic agent for Alzheimer's disease, and most of anti-dementia drugs are orally administered in tablet form. Drugs are administered to patients not only in the form of tablet, capsule, syrup and granules but also by injection, rectal administration, transdermal administration and the like with the proper selection according to the properties of diseases or drugs. However, it is difficult to orally administer anti-dementia drugs to patients suffering from the progression of dementia.
To improve convenience and compliance of patients by reducing the frequency of taking drugs and maintain the concentration of drugs continuously for a long time, it is believed that sustained-release injections are very useful. However, in the case of administering anti-dementia drugs to patients for a long time—for example, 4 weeks or more—it is difficult to make drugs be continuously and uniformly released while maintaining biological activities of drugs in the body. Accordingly, the need has grown for sustained-release injection of an anti-dementia drug having a property of stable drug release for a long time.
As for the prescription pattern of oral dosage form of donepezil hydrochloride, the usual prescription is first 5 mg of donepezil hydrochloride administered once a day at bedtime. This dose is used for 4-6 weeks, and donepezil hydrochloride is then increased to 10 mg and administered once a day. In the case of the first time patient in whom the treatment is carried out in such a manner, there is a shortcoming that drug compliance to daily oral administration is low. As a result, there has been a need to develop sustained-release preparations. However, there has been no report about development of donepezil as a sustained-release injection.
As an example of sustained-release preparation, Pengcheng Zhang et al. prepared sustained-release microparticles of donepezil and evaluated them (Pengcheng Zhang, Lingli Chen, Wangwen Gu, Zhenghong Xu, Yu Gao, Yaping Li, In vitro and in vivo evaluation of donepezil-sustained release microparticles for the treatment of Alzheimer's disease, Biomaterials, 28 (2007) 1882˜1888). They prepared microparticles containing donepezil by the use of copolymer of lactide and glycolide, but the content of donepezil in microparticles was about 13.2% and the loading rate was only 66%, so that there was much drug loss and a problem that too much administration amount was needed for practical application to patients.
As such, there has been a need for developing a sustained-release parenteral preparation of donepezil which is not administered in a large amount, has stable drug-releasing property for a long time and continuously maintains an effective concentration in the blood.